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Friday, September 28, 2012

Adam Van Arsdale, a biological anthropologist at Wellesley, and I had a little cyberside chat about some big issues we're facing in higher education. It's cross-posted at Adam's blog here.

Do you like the idea of online education?

Adam: On a theoretical level, yes. I like the idea of using technology to broaden the reach of higher ed institutions. The reason I became a college professor is, in part, because I love Colleges/Universities. They are amazing places full of incredibly intelligent and curious people. Broadening the reach of such places by making them more accessible via technology...that is an idea I can get behind. In implementation, however, I have a lot of doubts, questions and concerns.

Holly: No I don't like it, and that's probably mainly because it is alien to my perception of school and does not constitute, to me, a complete or fully engaged environment of learning.

School is full of sounds, smells, textures, air, and emotions and opportunities that come from sitting in proximity to other humans, learning among and with and from other humans, talking among others. School is where students can interact in person with teachers who are of a potentially unfamiliar demographic, with a different worldview, vocabulary, set of experiences, etc. than they may be familiar with. Performing experiments, painting, creating, and moving the body, all the physical work and physical learning. How does any of this take place online? And to restrict these physical practices to music courses and laboratories is bogus. We move about in my Human Origins class. I particularly value extemporaneous thought and the communication of it. I make students think on the spot and talk to one another and to me in class. If I don't understand or agree, I ask them to rephrase right there. I think that people who graduate from college should sound intelligent and should have the skills to clearly think quickly and then convey their thoughts spontaneously. How is this practiced online? And how do students present their work, orally, online? As a teacher, how do I imitate a knuckle-walking chimpanzee online?

I cannot imagine teaching anthropology online. Period. But even if I taught math, something I see thriving online on the education sites, I would still resist because I feel strongly about the human connection in real life being more constructive than anything that can form across cyberspace.

Adam: I also associate college with spaces, places, groups of people and experiences that could not possibly be replicated online. But I guess I don’t see online education as trying to replace or replicate that experience, but instead expand the idea of the College/University to something not bound by physical parameters.

The pedagogical issue of how to teach online is another issue altogether. Like you, I like creatively engaging my students. For example, as part of a first-year seminar course on the Anthropology of Food and corresponding to a discussion of the evolutionary origins of cooking technology, I held class around an open fire this week, complete with raw and cooked food. Not something you could achieve online.

That said, my teaching experience prior to Wellesley was, in part, teaching large lectures at the University of Michigan. These were classes with more than 150 students where I was responsible for designing all of the course elements and providing 2.5-3 hours a week of engaging lecture, but most of the individual interactions took place between the graduate student TAs working under me and the undergraduate students in the class. That style of teaching seems much more compatible with the current structure of online education platforms.

Holly: Your fire sounds great. I will copy that the first chance I can!

And, yes, that style you speak of in the last thoughts is more compatible with online courses. But although some students may learn a great deal from those big classes, that all-too common situation is not my idea of good higher education. Online education, to me, has taken so much of what is wrong with higher ed and turned that into a business model. It’s easy to see why. Many of these people in the business of online education probably got their degrees by sitting anonymously through huge lecture courses. Education, to them, was made for cyberspace!

But back down to Earth...Demonstration of independent complex and critical learning and thinking through extemporaneous writing is also important and these sorts of things cannot be done with the same kind of quality outside the classroom on the computer with books and Internet readily available for help. I do think that students should learn to be excellent seekers and identifiers of good information, because we can't all remember everything, nor should we have to when resources are at our fingertips thanks to the Internet, but I also think that students should be able to retain, evaluate, synthesize and explain information too. This is training for a life of the mind. This intense training, to my mind, cannot occur without a classroom.

Adam: Agreed on the sorting between the best and the worst of higher ed. I think the attraction of online education is often viewed as its scalability - the ability to take one great professor’s lectures and reach 10,000 people with them. That kind of scalability is, however, not very consistent with the best parts of higher ed, which are the individual working relationships between faculty and students. These are not only the kinds of interactions that predominate in the real world, but also the best way to teach.

One of my additional pedagogical concerns with online education is the potential for students to learn the information wrong. My biggest fear as an educator is not that students will not learn what I am teaching, but that students will leave my classroom having incorrectly learned what I teach them. I teach courses that deal with sensitive issues like race, intelligence and health and I regularly have students who, mid-semester, have gotten the information exactly wrong. This is the worst possible outcome. Meeting with students several times a week for 15 weeks has the advantage of ensuring that by the end of the semester there are very few, if any, students in this situation. The physical presence of the students helps limit this problem. With online students the ability to simply drop-out midway through the learning process seems greatly elevated.

Holly: Good point. And do you think that cheaper online education will become the only option for the less moneyed folks, while the ones who can afford personed, hands-on learning will get keep to the old way, but with fewer of the riff-raff around to get in the way?

Adam: I think this is a real issue. Most of the discussions around the “crisis of higher education” these days are not directed at the entirety of higher education, but rather at the widening class structure of higher educational institutions resulting from declining financial support for public universities. The potential of online education to crystalize the division between elite, on-campus student experiences and alternative online experiences seems real and worth considering carefully. But at the same time online education might (might) provide a way to expand higher ed opportunities to a larger fraction of the population.

Holly: Definitely. And it’s going to happen no matter what, but should we tolerate it? Should we restrict what I consider “real” higher education to the few who can afford it? This is antithetical to the whole point of it.

Further, people have their whole lives ahead of them to hunch over a laptop. Resist as long as possible! That's aimed at students, but what about us professors? Spending time on the computer to teach will suck up all the time and energy we put into writing papers and books. I know for me that if I have to spend more time on the computer for teaching online, my research and writing will suffer greatly. I cannot physically be at the computer so much. So that other part of my job, my purpose, would have to give.

Adam: I think we are on a ship that has already set sail in this regard. We are only likely to become more embedded with our technology in the future. I like to think of it in (pseudo-) evolutionary terms, imagining some poor human 20,000 years ago bitching about all the time his friend spends drawing on the walls of a cave... “If you want to see a wild auroch, why don’t you just come out here and look at the wild auroch.”

I place a tremendous value on my opportunities to go offline and take advantage of natural places (one of the reasons I love fieldwork), but I don’t pretend my reliance on technology in my personal and professional life is going to reverse its trajectory anytime soon.

Holly: I hear you but I physically can’t do it. I have cervical neck issues that immobilize me if I am at the computer too much or too long. Even if I stand. Even with ergonomic furniture. I cannot be the only one who suffers like this and resists the thought of a completely computer-based occupation, which for professors, is more than 40 hours a week.

I also worry that online education will mean fewer professorships (since an online course can teach many more, so fewer classes are offered; or conversely fewer will go into this business, preferring to work a different job than to teach online for little money). If fewer professorships exist because of it (and this would just complement the trend already going down) that will mean there will be fewer scholars which means scholarship slows down in those fields.

I also worry that teaching to more students by fewer educators will lead to a homogenization of knowledge, which to me spells h-e-l-l. And I don’t mean the same courses taken by every student, I mean the same (always limited and cherry-picked) content in those courses, with the same quirky theoretical biases! I would never take the job as the only or the main biological anthropology professor in the U.S. But that kind of thing could happen. Adam: I share this concern. Technology applied to teaching should be aimed at broadening its reach, not undermining its value.

Holly: But if we want to ready humans for a future that needs little real-world socializing, since it's a future of humans hunched alone over their laptops, and in this future everyone needs to know much more of the same things as one another to succeed, then online education seems like a great way to get that accomplished.

No, I don't like the idea of it.

Why go online with higher education?

Adam: I think the reason to go online is to broaden the reach of the wonderful things that happen at higher education institutions. Giving more people access to more knowledge and opportunities to learn is a good thing. I am skeptical of profit motives for doing online education. Certainly, there is a cost associated with producing high-quality online educational resources and platforms, and online programs need to be financially supported, but I worry that profit motivations too easily undercut quality considerations in an online setting. I think the goal of online educational platforms should be to produce as high quality a learning environment/product as possible and run it at a cost neutral level (compensating for platform development, support, teaching and related areas).

Holly: I think universities want to do it because it's cheaper for them and it's appealing for students who can't afford to live on campus and could save money on the commute if they can learn from home. This all makes sense for everyone except for society at large, for our future, for humanity, for higher education and all that magical stuff we're supposed to care about and that many of us really really do care about.

I do love the idea of being able to take a guided course in something that's not offered nearby or that you can't take nearby because of your work schedule. And as a continuing ed tool it's amazing. It just seems like, to me, for undergraduate education, online education is taking much of what's wrong with higher ed--the stuff about it that makes it a horrible educational experience for so many: huge "classrooms," very little extemporaneous speaking, little independent and spontaneous critical and synthetic thinking, etc, etc etc etc--and making a business model out of that!

Now, hybrid courses seem okay. Students meet a few times in person and then hold some designated course time online discussing the course content. I still wouldn't want to do this (see above), but it seems to really be a great system for the professors who I know who have implemented it. However, and I'm not a conspiracy theorist, but I worry that this hybrid thing is a wedge strategy by admins to get us to put entire courses online.

Adam: Again, I go back to the value-oriented motivation of expanding online education as a way of expanding the reach of higher education institutions, not increasing profit margins. Going back to our earlier concern about the number of jobs and compensation for professorial work, I like the model of online education expanding the customer base with a related expansion in the size of the profession. There are some potential cost savings in this approach in that eliminating the need, at least partially, for the physical structures of an institution lowers cost overhead. But generally, I think motivations to produce online education because of its increased profit margin are extraordinarily bad.

I also think, however, that the pressure to go online is growing tremendously for Colleges and Universities. My initial exposure to this area was in a job interview at a non-flagship state University. During my campus visit it was made clear to me that developing online courses would be part of my job. Here, the motivation seemed to be aimed entirely at enrollment and the related revenue and institutional clout issues that go along with having more students. But at my current institution, the consideration of going online seems driven more by issues of reputation. If the Stanford, MIT and Harvards of the world are going online, surely we need to as well simply to keep up.

To go online or not to go online...

Adam: I guess as a preliminary final thought, I hope that there is a movement towards more online, open access educational offerings by higher ed institutions. However, I have several caveats associated with that statement. I think the rationale should be based on expanding education opportunities and the associated fields of intellectual pursuit rather than creating a market for a degraded educational product. With this in mind, I am not sure that full, online courses, modeled after the kind of in-person courses currently being offered is really the best model (though it is a model that is rapidly expanding). I think we can be more creative in using higher ed institutions as generators of online educational experiences. In addition to the other fears articulated above, online education needs to be wary of vendors who are simply seeking to create systems of accreditation/certification rather than true learning experiences. As someone at a liberal arts College, I think our great strength is that we help smart people think creatively about how to use their intelligence across an infinite range of potential problems, not that we produce people with a specific degree.

Holly: I mourn for the loss of the college experience. And I don’t mean keg parties and football games (well, not entirely)... I mean the loss of the experience of active and engaged learning from marvelous humans. Dr. Indiana Jones taught in the classroom! He’s right there, erasing the chalkboard, collecting homework, recruiting future research assistants.

The college experience is incredibly exciting and reeking of potential opportunities for young people who don’t even know what those opportunities are until they arrive to college, until they get to interact with peers and professors with vastly different stories from their own. Going to college is traveling without a passport requirement. It’s priceless and it was open and available at relatively low cost to so many for so long and now it’s disappearing.

How much of my protesting is self-protection? How much of the changes to higher ed are just driven by whomever’s self-protection efforts (software companies, university admins) outweigh others? I don’t know. But I do know that my objections to online undergraduate education on educational grounds are valid and not just because I'm invested.

Thursday, September 27, 2012

Since Monday and Tuesday we've been trying to answer what seems like a very simple question: What are the odds of having different sex ratios in a five-kid family? Like, what are the odds that Ann and Mitt Romney had those five boys?

We started investigating this question because I was viscerally annoyed with the simple calculation that 1/32 is the probability that a family of five will be all girls or all boys. Those odds imply that it's rare when it should be just as likely as any family of five.

If you haven't read them yet, please see Monday's and Tuesday's posts before starting here. They're the start of this journey that I'm chronicling, ending with today.

We stopped on Tuesday with a change of strategy in estimating the odds of different family compositions. See my long list of all 32 possible series of boy/girl in a five-kid family and add up the ways to achieve the six different family compositions. Here are our results:

What are the odds that you'll get...5 girls, 0 boys? 1/325 boys, 0 girls? 1/324 girls, 1 boy? 5/32 (there are 5 possible series out of 32 that make up this boy/girl ratio in a family)4 boys, 1 girl? 5/323 girls, 2 boys? 10/32 (there are 10 possible series out of 32 that make up this boy/girl ratio in a family)3 boys, 2 girls? 10/32

(Psst. I googled how to calculate probabilities and found this website and DINGALING! they're actually using my example. And here's a nice site showing how to work with a binomial equation rather than list all the possible 32 outcomes like I did Tuesday.)

This sort of thinking about probabilities should remind you of how the odds of the outcomes of rolling the dice are not uniform across all numbers. Your best bet is a 6, 7, or 8 because there are more ways to get those three numbers than the others.

(The following list was edited thanks to a very nice comment, February 5, 2015)

(Psst. If you still think 7 is lucky for rolling the dice, then you should have more of a think about probability.)

And just like 6,7,and 8 from rolling the dice, having three boys and two girls (or three girls and two boys) has a "luckier" or higher probability, or more probable, more likely sex ratio in a family of five children.

How do we know which of the two sets of probabilities that I calculated--Tuesday's or today's--is correct?
All girls, no boys: 1/6 or 1/32? (17% or 3 %)
All boys, no boys: 1/6 or 1/32? (17% or 3 %)
Four girls, one boy: 1/6 or 5/32? (17% or 16%)
Four boys, one girl: 1/6 or 5/32? (17% or 16%)
Three girls, two boys: 1/6 or 10/32? (17% or 31%)
Three boys, two girls: 1/6 or 10/32? (17% or 31%)

I see very clearly why our second method (in bold) is superior to our first which was to incorrectly divvy up the odds in sixths. That is, I can see clearly why the odds of having five girls is still 1/32 and not 1/6. There are so many more ways to make a family of five with four girls or with three girls or with two girls than to make one with five girls, so you can't possibly have evenly distributed 1/6 odds for all those types of families of five children.

Initiate mind-blowing sequence.
But when you take the long view, 1/6 (or at least higher odds than 1/32) for a streak of five girls still seems not so crazy.

After all, the odds of having five children of all the same sex are only the lowest, the rarest, becuase we've arbitrarily decided that our family in question maxes out at five!

Would we find those same low odds of 1/32 for five girls in a row if the family had six kids--having more opportunities to have streaks of five girls during that span?

That's (a +b)^6 and if you scratch it out on a piece of paper you don't need to expand the binomial equation. Odds of having six straight girls is 1/64. Same for any series you can make out of six births (all of which add up to a total of 64 different series of boy/girl adding up to six kids).

And then by just sketching or scribbling (but if you're fancy, you can also just use the binomial) you can see how you can get only three series (gggggg; gggggb; bggggg) to have five girls in a row to occur in a family with six births.

That means the odds of having a streak of five girls in a six child family is 3/64 which is 4.6875% (compared to 1/32 or 3.125% in a five child family).

So the odds are slightly larger in a bigger family.

Wait. Did I just do that right?

Let's try a family of seven to make sure I did.

Here are all possible streaks of five girls in a family of seven...
ggggggg
ggggggb
bgggggg
bbggggg
bgggggb
gggggbb
gggggbg
gbggggg

The odds of having five girls in a row in a family of seven = 8/128 = 6.25%

Okay, with a bigger family, the odds are even larger.

What about a family of eight? The odds of having five girls in a row in a family of eight = 19/256 = 7.4%
(Trust me... I scratched it out. And it could be more than 19/256, but my contacts fogged up before I could find anymore.)

Okay, yes. The odds of having a streak of five girls increase as the size of the family increases.

Wait. What?! How do odds change? Odds are odds?

Instead of going up in scale again to check, making calculations even harder, let's go down in scale to check our math. We already know from Tuesday that the odds of a five-kid family having a streak of four girls is 3/32 (ggggg; ggggb; bgggg) = 9%.

Okay, now what about in a four-kid family? The odds of having four girls in a four-kid family are 1/16 = 6%.

WHAT?! Just by making a fifth baby, you've just seriously upped your chances of having a streak of four girls. Your odds go from 6% if you max out at four kids to 9% if you max out at five kids. That sounds reasonable, but...

This means your odds of having a streak of four girls or five girls (or anything!) depend on what DIDN'T YET HAPPEN IN THE FUTURE.

I'm sorry. Hold on. Time out for a sec. My brain is literally inside out right now.

Am I seriously figuring out now--Today. This minute.--that probability is vulnerable to what hasn't yet happened in the future? And that the present can change past probabilities?

That sounds so familiar. That idea. But never do I think I've ever come to it by myself.

Until now I think it was always just a sentiment that Deepak Chopra hugged into to Oprah who gifted to Martha Stewart who baked into a lemon zest fortune cookie.*

So predicting or estimating frequencies can change by the very nature of the present? Very interesting.

Doesn't it sound like we're crossing streams with the whole quantum mechanics pickle about changing a particle's state the moment it's observed? (and here)

Are people just particles?!?!

(yes)

Am I on psychedelic drugs and where can you get some too?

This shouldn't be so bleeping mind-blowing should it?

Unless... unless... As my repulsed reaction to a snappy "1/32" indicated at the outset back on Monday: Small scale probabilities are different from large scale ones. Probabilities become different the bigger and bigger that you get.

And it's no secret that people who think evolutionarily think big. We're transcending space and time constantly. What? We are. You're welcome to join us. It's fun here. No vomit comets necessary either.

So if we approach 100, 1,000, or say... um... just to pull a random number from the air... SEVEN BILLION births, we should expect to have a much higher than 1/32 chance in finding a streak of five girls.

True. Nobody's making a family of seven billion children. So the question is, do we treat each family as defined by a finite probability or do we see births and families in our species as part of one big series with vastly different probabilities at that level than at the level of the family?

If it's the latter, we should expect what, exactly? Greater odds than 1/32 for having five girls in a row that's for sure ... Greater than 19/256 that's for sure ... The odds are x (where x = ways to make 5+ girls in a row out of 7 billion) divided by 7 billion and so they're going to be greater than 1/32 by a long shot! It may even be close to our earlier totally gauche calculation on Tuesday of 1/6 or it could be even higher!**

So why do we even calculate odds at the family unit level? Just to practice our algebra? Are they really as meaningless as my gut was screaming out in Monday's post?

No no no. I know why we calculate them in our math workbooks and our homeworks. It's not just algebra practice, these are hypotheses we can test.We can use these expectations to see whether there is any factor skewing the outcomes of some families, perhaps there is something biochemical in the babymaking process that results in one kind of offspring for some parents. We'd have to look at families (to account for genes, etc) or at clusters of people living in the same environment (to account for bio-enviro interactions). If we find that within those sorts of sample populations people are having an unexpectedly high number of all-girl families (i.e. there are significantly more than 1/32 families of five children who are girl-only), for example, then we might suspect that there is not a 50/50 boy/girl probability with these folks each time they make a baby and that might entice us to investigate further into their genes or into their ground water, etc.

But back to these issues about small versus large perspectives that we've uncovered here...

In general, we might find 1/32 five-girl familes of five kids max in our species, but if you look at a hospital register, for example, we'll find streaks of five girls much much more frequently than 1/32 (3%) of the time.

There is something misleading about the way we calculate probability in a closed and narrow view of the world. And there is something subtly different about thinking probabilistically about a series of independent events and thinking probabilistically about their outcomes, instead, especially when many separate series can have the same outcomes (e.g. rolling a 7 with the dice or having 3 boys and 2 girls).

I think I've located my trouble with probability. It's just a small one with having a large denominator. You know, something pretty easily surmounted--it's just grasping silly little old infinity's all.O! Maybe later I'll see if I can dig up what the demographic data say. I can ask: How do the frequencies of sex-ratios in human families fit these tight little closed and narrow probabilities/hypotheses? And do birth registers in hospitals show something much different, probably larger? I shall hope to find out. Not because it's a mystery; I already believe I know the answer. But because I can't simply believe to know an answer if there is a real way to see one, and there is a way in this case, so I should go and see in order to believe.

Thanks for reading. Hope our little journey back in time to the fundamentals of statistics blew your mind even a fraction of the way it blew mine!

Further humbling questions and related thoughts are increasingly probable to appear in future posts....

Wednesday, September 26, 2012

A piece in "Inside Higher Ed" describes the frantic race by the 'top' universities (self-proclaimed) to put their courses in the MOOC (massive open online courses) category, perhaps an inevitable outcome of the unrestrained onlinification of the world. The Bezos or Google mentality is taking over -- pull the rug out from under the stodgy competition and take virtual control. We quote the story at length because, well, because it's pretty jaw-dropping.

Coursera [a major provider of online courses] continued its ambitious expansion in the growing market for
MOOC support today, announcing accords with 16 new universities to help
them produce massive open online courses — more than doubling the
company’s number of institutional partners and pushing its course count
near 200.

The new partners include the first liberal arts college, Wesleyan
University, to leap formally into the MOOC game, as well as the first
music school, the Berklee College of Music.

Coursera also announced deals with name-brand private universities,
such as Brown, Columbia, Emory and Vanderbilt Universities; some major
state institutions, such as the University of Maryland System, the Ohio
State University and the Universities of Florida, and California at
Irvine; and several international universities, such as the Hebrew
University of Jerusalem, Hong Kong University of Science and Technology,
and the Universities of British Columbia, London, and Melbourne.

The company already boasted the most courses and student
registrations of any MOOC providers, having registered 1.3 million
students for its courses (although far fewer have actually stuck with a
course). Andrew Ng, one of its co-founders, said Coursera will probably
double its university partnerships at least one more time before it
stops recruiting new institutions.

Is this move dwarfing any other kind of academic reform than universities might think up? Like actually requiring students to do some work, such as we posted about recently?

MOOCs are free, but if you want credit you have to pay. Maybe it's the ultimate come-on tantalizer. Can they deliver good education? Time will tell, but the major questions are first, whether the level of education will typically be close to that students can get from face-to-face contact in class, and whether this will undermine universities across the country (and world).

Will 'Bezos University' mean that local real colleges and universities can dump much of their faculty? Will on-campus work consist mainly of things that require physical presence, such as labs or perhaps art museums? Will that be restricted to the elite who can pay?

There are the large threats from online enterprises, such as the ones to whole industries -- Amazon and publishing houses, e.g. -- and there are smaller threats, as to local theaters from the distribution of live broadcasts of the Metropolitan Opera. If this, e.g., is a money raiser for them, and it seems to be since it's been going on for a few years, then are local musical companies being squeezed out of business? If you can see prima donnas on the Big Screen with great sound and subtitles, why pay to see lesser local singers ply their trade? Or will the telecasts whet the appetite for in-person theater?

We don't know the answer, but the issues are serious. We are training gobs of graduate students across the country, largely aiming them at academic jobs. Will those jobs be there? Or will the jobs be much lesser ones, of doing online tutoring of the students who pay for downloads of the 'real' professors who are professing on Bezos U?

Time will tell. It doesn't seem the train can be stopped, as every me-too university that can join the online club will frantically do that so they don't get left behind. This is not based on anything reasoned or rational at this stage, but purely on the 'business' model of education.

Tuesday, September 25, 2012

We're in the middle of a three-part post on simple probabilities. If you haven't, please see yesterday's to get up to speed.

How many ways can you make a five kid family?
First order of business: Remove head from gutter.
Second order of business: Make sure 1/32 is correct.
Let’s see if there really are 32 possible outcomes when a couple has five kids. And let's see if whether having all boys or all girls is a 1/32 shot.

Count all those up and there really are 32 possible series, or possible outcomes, when a couple has five kids.

However...

Independent probabilities
Does this mean that if you’ve had four girls and you’re pregnant for a fifth time that you have 1/32 odds (3% chance) that it will be a girl? Afterall, having five girls has only a 1/32 chance to it. So does being pregnant after four girls mean that you're probably going to have a boy? Are the odds are on a boy's side?

Of course not.

Each babymaking event is independent. Each is 50/50 odds of boy or girl. Even after four girls you have a 50% chance of having another girl. Just like every single other time you made a girl before.

Think about that if you're really really in the mood for a boy after four girls. Are you still interested in having a fifth kid that still has 50% chance of not being the boy of your dreams?

Look. Lots of people know this already and very well, but that doesn't stop them from being seduced by trends, streaks, runs. This is momentum or luck that is most probably not real, yet it can be so very intoxicating in a casino. By having a fifth pregnancy just because you want a boy, you are playing the odds--the same odds you've had each prior birth.

One in 32 has absolutely no meaning to you unless you’re thinking of your family in greater context, in terms of all the families that have ever had five or more children and what their outcomes were.

The odds that you had five girls out of five were 1/32 but so were the odds that you had girl, boy, girl, boy, girl!

Going from series of births to sex ratios in families
Calculating the odds of having x girls and y boys for a total of five kids (x + y = 5) is a different estimate indeed. One way to consider this estimate is that there are six possible boy/girl ratios in a five-child family...

5 boys, 0 girls

5 girls, 0 girls

4 boys, 1 girl

4 girls, 1 boy

3 boys, 2 girls

3 girls, 2 boys

So that's 1/6 odds, or 17% chance, that if you have a family of five children that they'll be all boys. These are the same exact odds that you'll have any other combination of boys and girls totaling five children.

But wait.

It's obvious that there are more ways to get to some boy/girl ratios than others. There is only one way to make a family of five children with five girls (5g, 0b). But there is more than one way to make a family of five children with three girls (3g, 2b). Let's add those series up and get some different answers with this different line of thinking...

Monday, September 24, 2012

As is tradition in the blogging world, I'd like to note that yesterday marked the start of my fourth year writing here at The Mermaid's Tale and I couldn't be more grateful for all of the wonderful things this experience has brought to me over the past three years. Thank you Ken and Anne and thank you readers.

After that preamble, today's post requires its own preamble as well.

I'm writing a popular science book about subjects that are so far afield that I will most certainly embarass myself. But it's for good cause. It's subject matter that anyone who's interested in human evolution (and sex) needs to cover and no one has. Enter my dumbass. Enter my concept of "reproductive consciousness."

Anyway, in further preparation (as if 35 years hasn't been enough) for the droplets of flopsweat sure to pour when my book is published, here's a peek at Yours Truly wrapping my head around a fundamental concept that I take for granted every day and thought I'd gotten a grip on back in high school, if not before:

Intro, context, yadda
I had just asked if anyone at our lunch table knew of a decent TV news program to watch while exercising in the mornings, since I was--hours later--still traumatized from watching the hosts of Good Morning America read Hannah Montana's existential tweets with their journo-sylLAHbles.

Needless to say, we all decided that the newspaper and NPR are the only morning news options.

Naturally this lead me to remember a quality story and discussion I'd heard from the BBC on NPR about the latest in "designer babies," which is to say the latest methods for controlling the genotypes of offspring and the ethical issues and debates over it all. This particular story was about taking healthy mitochondria from one female to replace harmfully mutated mitochondria in a mother who wants to have healthy babies but with her own nuclear DNA. Or, alternatively, taking a donor embryo from a woman with healthy mitochondria and replacing the nuclear DNA with the parents' who are trying to conceive a healthy baby.

And the controversy about that led me to share what I'd learned in another story recently on Slate--a practice that seems more deserving of the criticisms described in the BBC story. In this instance, the harmful mutation is an entire chromosome: the unwanted Y or X, depending on parental desire. And biotech has advanced far past separating the heavy slow swimmers (X sperm) from the fast nimble ones (Y) and only allowing the one type to enter the race to the egg. For those who are desperate to control the outcome, you can now test the embryos directly and implant only the ones with the desired pair of sex chromosomes.

Now if you're one of those people like in that Slate story who's just dying to have a girl so you can do makeup and hair with her, I hope it's obvious that although you may be closer to your dreams with this sort of genetic control, you're still not guaranteed to hit the baby jackpot simply by getting one with an XX. There are lots of XX humans who would rather curl up and die than curl their eyelashes or dye their hair. And, on the other hand, there are lots of XY who fancy it. There is nothing on the X or Y chromosome that anyone has linked definitively to the proclivity for behaving in these sorts of gendered and cultured ways. [Except indirectly of course, by priming an individual to be gendered and cultured according to whether they have boy or girl anatomy.]

Further, even if there is a genetic component involved in affinity for doing hair and makeup, this method for choosing baby sex isn't typing or sequencing any genes! It's just dealing with the whole chromosomes, and even if it was typing or sequencing the genes on the chromosomes for such behaviors (if there are any such genes), those genes would still only indicate a probabilistic phenotypic outcome, not a determined, certain one. Other parts of the genome as well as the epigenome, microbiome, environment in utero and beyond, including interactions with humans and their behaviors... these factors and more contribute to these sorts of complex behavioral phenotypes.

So I hope that parents who are putting $18,000 dollars towards making sure that their child has XX chromosomes know that the genotype is only probabilistically linked to certain parentally-desired phenotypes. That's not just a large financial gamble (well, for most Americans), but it's also a huge gamble with someone's life, someone who's sitting completely vulnerably and literally in your hands for the earliest years. That gamble piles on top of the risks (to parents and the new human) already inherent in making a new life in the first place. No matter how much money you throw at biology, you can never contain all the probability. But I guess if you have 18,000 bucks you can get the probability to lean towards your dreams.

If you sensed a bit of prickliness here, it's for two reasons: The biological complexities to be sure, but also my lack of empathy for these sex-obsessed parents. It's hard for me to imagine creating and clinging to such specific dreams about uncertain biological and cultural outcomes rather than simply being hopeful that you'll be pleasantly surprised and then mostly happy with whatever uncertainly happens and unfolds in life.

But that's not even what got me to write this post, if you can believe it
While on the topic of choosing your baby's sex, a colleague who's one of five girls shared a good question: Within couples, is there a biological basis for a sex bias? She wondered if there could be some reason that a child from a particular couple might not have a 50/50 shot at being a boy or a girl. She wondered if something about a couple’s chemistry skewed the odds towards one sex and that this could explain why some families have a biased sex ratio, like hers with five girls.

That’s a good question and the first thing you'd have to do before you start investigating is you'd have to calculate the probability of having five girls, particularly five kids who are all girls. That way you could test your estimated, expected frequency against the frequency that you later go out and observe in nature.

As we began down this thought-experiment rabbit hole--mentioning first, of course, how there’s 50/50 odds at each birth--a colleague quickly mentally calculated that the odds are 1 in 32 for having five girls and no boys.

Yes: (1/2)^5 (i.e. 50% times itself five times) gives you a 1 in 32 chance (roughly 3%) of having five girls.

But this sounds way too rare. If odds are 50/50 each time you make a baby and if events are independent, that is the odds do not change based on prior events, then how could the odds of having five girls be so small? How could it be any smaller than having any other kind of family? The odds for all families should be the same.*

I was simultaneously reminded of so many correct answers I’d rotely written in math and stats courses, while also feeling completely repulsed by the theory. What kind of meaning does 1/32 contain? It seems like nothing! Each birth is a discrete event. No outcome of prior births have anything to do with the odds that each birth will be 50/50 odds a girl. So how does multiplying their odds together in a string tell you anything meaningful except that we're so clever we can multiply fractions together and come up with a smaller chance for a series of events than for a single event? Isn’t this basically biological meaningless information? Whenever I feel this vehemently frustrated I should probably figure out why, and I may as well drag you all along for the ride in case you can empathize or in case anything I uncover helps you too.

Friday, September 21, 2012

We may have fewer posts in the next couple of weeks, because we'll be in Berlin, where I'll be co-teaching a week-long mini-course called 'Logical Reasoning in Human Genetics.' We'll try to blog about issues and so on that arise there. Meanwhile, Holly's already got a lot lined up so do stay tuned.

'Logical' reasoning is designed to raise the issues about knowledge and how we get and evaluate it in human genetics. Of course, we'll stress the issues related to causation and complexity, and how that involves genetics. How do we gather evidence? What theory--if any!--do we use to evaluate that evidence? One of the core criteria for modern science for the past 400 years has been prediction, that is, that from a given set of observed conditions we can predict future outcomes (the manifest objective of 'personalized genomic medicine'), then what is the basis of the belief that this is actually true, or that its truth will be broadly applicable?

These seem like simple questions, but they depend on the degree to which Enlightenment-derived criteria for making inferences about the world apply to the genomic world.

Likewise, the same issues arise when we try to understand and reconstruct evolution, both generally and in particular from a genomic point of view.

As time permits, we'll blog about these things here in the context of trying to raise them for the professional or pre-professional students who take this course next week.

Thursday, September 20, 2012

The cause of chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME) has not yet been identified, but a non-cause has been. A 2009 paper in Science suggested that the disorder might be caused by an infectious retrovirus. This made sense clinically because many patients report having a viral illness before becoming ill with CFS/ME. From the 2009 paper:

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown
etiology that is estimated to affect 17 million people
worldwide. Studying peripheral blood mononuclear
cells (PBMCs) from CFS patients, we identified DNA from a human
gammaretrovirus,
xenotropic murine leukemia virus–related virus
(XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%)
healthy
controls. Cell culture experiments revealed that
patient-derived XMRV is infectious and that both cell-associated and
cell-free
transmission of the virus are possible.
Secondary viral infections were established in uninfected primary
lymphocytes and
indicator cell lines after their exposure to
activated PBMCs, B cells, T cells, or plasma derived from CFS patients.
These
findings raise the possibility that XMRV may be a
contributing factor in the pathogenesis of CFS.

The investiagors also found evidence of pMLV (polytropic murine leukemia virus) in some patients. This work gave many people suffering from this disease hope that now the cause was known, and so a cure might be just on the horizon. Many began to take anti-retrovirals in the belief that, as for HIV, this could stave off the illness. Clinics were established to treat CFS/ME with anti-retrovirals, and public health concerns were raised over the safety of the blood supply with respect to XMRV and pMLV.

But many scientists weren't convinced that XMRV was the explanation, and a number of subsequent studies failed to confirm the finding. And to make things even more confusing, some labs could readily detect the virus and others couldn't find it at all. We (and many others) blogged about the confusion at the time, here and here. Indeed, analysis of the complete XMRV genomic sequence suggested that the virus was an artifact of a laboratory recombination event that took place around 1993-1996, and these investigators concluded "that association of XMRV with human disease is due to contamination of human samples with virus originating from this recombination event."

Well, now a new multi-institutional study now proposes a definitive answer. The investigators who originally found the retroviral association "report that a blinded analysis of peripheral
blood from a rigorously characterized,
geographically diverse population of 147 patients with CFS/ME and 146
healthy subjects" finds no evidence of XMRV or pMLV.

The paper concludes that the original finding was an artifact of the use of sensitive molecular methods, PCR, that can essentially make mountains out of molehills. Small amounts of contaminant can appear to be causative with these techniques and pose expensive difficulties for public health as laboratories go through the "pathogen dediscovery process."

We have often said here on MT that although one of the cornerstones of the scientific method is falsiability (yes, this can be and has been disputed, but it is certainly still considered by many to be so). Even so, many scientists cling to their original hypotheses even in light of very well-demonstrated refuting evidence. Thus, it's good to see this statement now, from the author of the 2009 Science paper that suggested the link between CFS/ME and XMRV, as reported in ScienceDaily.

"I greatly appreciated the
opportunity to fully participate in this unprecedented study.
Unprecedented because of the level of collaboration, the integrity of
the investigators, and the commitment of the NIH to provide its
considerable resources to the CFS community for this important study.
Although I am disappointed that we found no association of XMRV/pMLV to
CFS, the silver lining is that our 2009 Science report resulted in
global awareness of this crippling disease and has sparked new interest
in CFS research. I am dedicated to continuing to work with leaders in
the field of pathogen discovery in theeffort to determine the etiologic
agent for CFS."

The problem with falsifiability
Falsifiability was advocated, largely by the philosopher Karl Popper, on the grounds that induction--repeatedly observing the same thing--was not a reliable criterion for inferring something about the world. The reason is that the next observation could be different and ruin the generalization that had seemed true.

The idea is that one can never show something to be true--indeed, tomorrow the same data could be shown to fit some different idea from the one you had. But, at least, you could show your idea to be false. That is, you set up a test and expect the result your generalization would predict....but you get some other result. That leads you to develop a different idea (hypothesis) about what is going on.
If one idea after another is falsified in this way, then this is a systematic way to approach knowledge, because whatever explanation remains is more likely to be the true one (this is essentially what Sherlock Holmes said, long before Popper ever came up with the idea!).

But experiments can fail, studies can be poorly designed, and so on. As we noted, scientists tend to use those explanations when the result isn't what they want: we need bigger studies! This negative study was not properly designed! The methods were not up to date! And so on... This makes science a social and political, rather than strictly objective and empirical, form of human endeavor.

That's why falsification is just not a definitive criterion. In this case, the author has given up on the idea and is just grateful that people are thinking about the problem. Previous studies that did not confirm the hypothesis, however, were not considered robust enough to actually falsify it.

The deeper problem is that we have no definitive criteria for making conclusions in science. We do it by some informal, usually temporary, consensus. Maybe there will be found some truly definitive way to make inferences. Or, maybe science as a social and political activity is either the right way, or even the best way we can get.

Wednesday, September 19, 2012

Cells differentiate and specialize within organisms by expressing different genes as they develop, so that one stem cell becomes part of a thigh muscle and another part of the thymus gland. But what makes organisms like bees specialize? Some are foragers and some are nurses, and most switch their specialties during their lifetime, sometimes a forager, sometimes a nurse. Queens are committed for life, and it has long been known that royal jelly makes a queen, but how does a bee become a nurse and then a forager? And why are these roles reversible?

A paper published online in Nature Neuroscience September 16 by Herb et al., and reported on the BBC here, says that these behaviors are the result of epigenetic signaling. That is, it's not heritable DNA sequence differences that create castes, but chemical alterations to DNA within the bee's lifetime through the process of DNA methylation.

DNA methylation affects gene expression rather than DNA sequence, but since it affects gene usage it is certainly valid to consider it 'genetic' in the functional sense of the world. But many people use the word 'genetic' to refer to heritable variation, passed from parent to offspring. One key thing that is being demonstrated in many ways is that the methylation patterns themselves can be inherited. Effects of genetic modification of this kind can affect traits--like disease susceptibility among many others--and be 'remembered' by the person who inherited a particular genomewide methylation pattern, and that pattern then transmitted to the offspring. A recent study in experimental flatworms is that this can happen for many generations. That, in a sense, is the deeper importance of DNA methylation. Whether or not that's happening with bees is another question.

Herb et al. analyzed methylation patterns in tissue from the brains of honeybee queens and workers, but found no significant differential methylation rates (DMRs) between them. Most workers start life as nurses, caring for the queen and larvae for 2 to 3 weeks, at which time they transition to foraging. Comparison of DRMs between worker subcastes revealed 155 DRMs between nurses and age-matched foragers.

These differences might have been due to the caste transition itself rather than the state of being a forager, but the authors tricked foraging honeybees into transitioning back into nursing the queen and larvae, and determined that the DMRs are linked to the phenotype, not the transition. They replicated their experiment to demonstrate consistency of results, and determined that reversion from nurse to forager reliably re-establishes methylation of many of the same genes, including one associated with learning and axon migration in fruit flies.

They also found evidence of a high frequency of alternative splicing in DMRs, that is, changes in gene expression that come about by the same genes being transcribed differently, probably in response to methylation.

This is all interesting in its own right, but as we often say here, it's further evidence that as we understand more about biology it becomes more complex, not less. DNA methylation assays are hot right now, but it has been clear for a long time that there aren't going to be genes 'for' most traits and behaviors, that something else, or numerous other things will be involved. Methylation may be a part of that repertoire, but like single genes, or single nucleotide polymorphisms, it won't explain everything.

Tuesday, September 18, 2012

"Small genetic change has heavy consequences," says the headline on a PR release from the University of Queensland, one of genetic epidemiologist Peter Visscher's academic homes. Further, the release goes on to say that "[o]ne small change to the DNA sequence can cause more weighty changes to the human body, according to a new study..."

Has the gene for obesity been identified perhaps? Well, no. Even the release doesn't actually claim that. Rather, if you look at the actual paper, published online in Nature on September 16, the research group reports, from a meta-analysis of 38 genomewide association studies (GWAS) of variation in height and BMI, that they've found a SNP in the FTO gene that they say is responsible for variation in BMI, body mass index. The FTO gene, or fat mass and obesity-associated protein, codes for an enzyme associated with regulation of food intake. Variation in BMI in the group with the obesity-associated SNP variant is about 7% greater than those without, and people with the variant are, on average, about a whopping 0.5 kg heavier than people without. Visscher, one of the co-authors on the study, says that this is important "because it demonstrates that genes can be found that affect trait variability."

That is, if there is phenotypic variability in a trait for which the genotype is presumed to be known, this could indicate a gene by environment interaction affecting the phenotype. This is known as the "reaction norm" of the genotype: a tree will be tall and straight in low altitudes, but the same tree would be short and wide higher up, for example.

Visscher goes on to say that the study provides an indirect way to get a handle on genotype by environment interactions, although they did not directly measure environmental variables so can't say this definitively. But, he says:

“For example, if the effect of a gene on weight is smaller in people who
physically exercise than in people who do not, then this will lead to
less variation among people with two copies of the weight decreasing
variant.

This has no necessary connection to the environment, except if we understand that the rest of each person's genome is part of the FTO's environment. The physically external environment, perhaps the internal bacterial environment, and the genomic environment are all involved. This doesn't change the point of the story, however.

Unlike the press coverage of this study, the co-authors downplay the significance of their findings with respect to explaining variation in BMI or height, and report that they haven't actually tested or found any gene by environment interaction to explain the modest effect of the FTO SNP that they did find. Possibly it is the genomic variation that, in the context of one of the FTO variants, leads to more trait variation than the same genomic variation in persons with the 'normal' FTO variant.

The paper concludes:

Overall, our findings are consistent with a low heritability of phenotypic variability and no common genetic variants that account for a large proportion of
variation in environmental or phenotypic variability. They also indicate
an absence of widespread genotype-by-environment interaction effects,
at least for height and obesity in humans and with interaction effects
large enough to be detected in our study in which specific environmental
factors were not identified. Nevertheless, the demonstration that
individual genetic loci with effects on variability can be identified
with sufficiently large sample sizes facilitates further study to
understand the function and evolution of the genetic control of
variation.

But this is (forgive us) culpably overstated!
Genes code for proteins and they interact with other things--often, they're catalysts which means they affect the rate of other reactions in the cell. Or they interact with other proteins, in ways whose efficiency depends on how tightly or effectively they bind with each other, or with DNA, or other cell products. Expression levels of a gene are similarly about quantity of effects. This means, almost by definition, that genetic variation affects variation, depending on the other things most any gene has to interact with. Further, most disease effects associated with genes (or their interaction with environments) affect the age pattern of onset of traits like body weight, or of disease. Again, these are quantitative effects on variation.

Roughly before WWII, Native Americans and 'Hispanics' who are admixed with Native Americans and Europeans, had very little diabetes or gallbladder disease and had a more typical body shape. Since 1950 or so, they have experienced a near pandemic of such disorders, with morbid and even lethal consequences. And increased BMI is one of the well-known, classical effects of this (a topic on which Ken has written for many years). There is no absence of GxE evidence! One would say there was only if one is, as this study seems to be, only dealing with present-day populations.

The main author of this paper is a very capable scientist, working in Australia. And surely he knows that the same kind of thing absolutely and in well-documented fashion, applies to the aboriginal population of Australia.

So, then, why is this paper significant? According to the authors, it's because they've shown that individual alleles can be responsible for variation in phenotypic variation. Important? New? You be the judge.

We should conclude on a more positive note. We don't challenge the results, which seem perfectly reasonable: FTO, one of the clearest and most replicated obesity-related genes known, has only a tiny effect as the authors have noted, and the extra variation means that the variant SNP allele has little if any predictive value. Yet genome-based prediction is what you're being sold by the science these days.

Our point is to challenge the overstatement,
which we think is part of a systematically misleading campaign to
geneticize almost everything.

Monday, September 17, 2012

Well, Penn State finally won a football game, and this is likely to reinforce the football-is-all culture around here. The Sandusky scandal has led mainly to the university implementing bureaucratic and public-relations reactions, and widespread denial-based criticism from alumni and other 'intellectuals' with some connection, even if it's only that they like tailgate parties by the stadium.

This week's NY Times Magazine has a story about the attempt to fire the University of Virginia's President, how protests reversed that decision, and how UVA seems to be going, if more slowly, in the direction the trustees wanted anyway.

At least UVA has only 10,000 students, while places like Penn State have 45,000 or so. Public universities being run as businesses are oxymoronic, and are frantically trying to respond to the loss of the social contract by which they had received public support. They are encouraging out of state students to come--for the deeply intellectual reason that they can be milked for higher tuition. They are all going to me-too their way online, as if there were a legitimate academic reason for it (whatever any actual reasons, and that's unclear, the often unstated motivation is financial).

Of course, the major universities have drifted more and more towards 'research' which is a mix of pressuring faculty members to be sales agents (generating overhead for the administration to play with), glamorizing 'research' (most of which is, when you look carefully, rather narrow, restricted, and trivial) over teaching. External funding, grant money, is often spoken of as if it is about quality, but again it's largely about money/overhead. And in the process, we increase the number of students, contribute heavily to the notion that a college degree is necessary for a successful life, and other business-model spin.

So this all leads to debate about the business model and how it should work, and what is the best strategy in the absence of state funding. Unfortunately, something is being lost in the shuffle. It's called 'education'.

How not to run a railroad
The crisis too often being spoken about when education issues are discussed is the fiscal one, arising from the growth ethic. But the more important crisis in the long run is simple: our expectations and standards have been eroding for decades. Students are entering college knowing less, too many with less basic ability because high schools and earlier aren't doing their jobs, they aren't studying as hard, and they are learning less. They get their degrees from the mill, but even in the good universities, like Penn State, every year many cross the stage to receive their college diploma....barely able to spell 'college diploma'. We are dropping the ball--and we know it!

Only the bold, the best universities, are likely to have the quality and the guts to reinstate higher academic standards. Or, the old line elites will do it, while the wannabees will talk about doing it and pay PR firms to say we're doing it--and remain in the subordinate social and economic class. Or, nobody will really belly up to the problem until China, Brazil, India, Europe, and so on make it clear that we've fallen so far behind that we can't compete any more and our standard of living erodes materially.

This may seem like a panicky kind of over-reaction. After all, we do have some very good students, some of whom can read and write and do math and who actually work hard at learning. Many are even academically honest! Maybe, even if the average has sunk, that's because there are too many here who weren't in college in days past, not because high achievers have become less numerous. But when study after study shows decline, we should at least think hard about doing something about it.

Relevance to you
This is a rant of sorts, of course, but it is relevant to many MT readers who are academics themselves, and it's also relevant to others, because this country depends on the skills of its people and they depend on skills for jobs. Not all people need college degrees, even if everyone should learn to read and communicate and calculate and so on for many of our daily activities, for many trades and professions, to be good citizens wise enough to see through political baloney, and to have enriched life experiences.

But some do or should have formal college-level education, and for them--and for the high tuition being demanded--we in the business should have an obligation to provide it. Undergraduates become graduate students, but we know they (too often, unless they come from other countries with higher college standards) enter graduate programs short of breadth of knowledge and often short of basic technical skills. Of course also, this begins with K-12, which may be the most serious issue we face--and our schools of education are perhaps especially culpable, and need to do something about it! It seems, however, that nobody has the will to confront these issues head-on.

There is even a foundation that is paying entrepreneurs to drop out and get to real work--following the Bill Gates, Steve Jobs and others' model of success. Meanwhile, if you want someone to fix something, like a leaky roof or refrigerator or computer, good luck! They've all gone off to get a college degree....

Friday, September 14, 2012

Exposure to X-rays can cause cancer, so their use as a routine and repetitive screen for tuberculosis (and, for readers old enough to remember, to look for the fit of shoes at a shoe-store), or for routine CT scans, and so on, is questionable. Dental x-rays seem to be so safe that their risk, which is probably not zero, is nearly unmeasurable and presumably worth the dental problems they can find (hopefully, though not certainly, they are not taken too often as a source of profit).

Developing breast tissue in young girls is vulnerable, so they were not routinely given chest x-rays. But breast cancer is common and serious, so mammography was seen for a long time as clearly a valuable life-saver, if used on peri- or post-menopausal women. But recent studies have raised questions. Interestingly, this is not because of new cancers that may be caused by the screening (though the number may not be zero). It was because they could detect small anomalies that were then followed up. Some would turn out to be cancer, even if in an early stage. But the follow-up is psychologically traumatic and has its own unexpected consequences. And even more, studies have shown that some of these cancers would regress on their own. So mammography, despite so many being convinced of its value, is now under scrutiny: when and how often and on who is this false positive risk too great to justify routine mammographic screening?

PSA testing has become routine for finding prostate cancer in older men, because prostate cells that are too active churn out PSA (prostate specific antigen), so high PSA levels, just as with suggestive mammograms, have been considered indicative of the need for follow-up. Again, that has its own morbidity--including, gulp, impotence!--so it, too has come under scrutiny. Indeed, as with mammography, studies have shown that the intervention's risk and the fact that many of the tumors would regress, or would stay silent until some other cause took the poor guy away, suggests that routine PSA testing be stopped.

Now, a new report suggests the same thing for ovarian cancer screening. The reasons are the same, and surely there will be as much controversy. What is this all about, and what is one to do, and why do we see this? Surely and hopefully, it cannot be all, or even primarily, due to the profitability of screening services and follow-up.

More likely this reflects the belief in technology, fed by and into the hunger for early diagnosis and treatment of very nasty diseases that threaten the quality of life or even life itself. Is it that early ideas about what might be early risk factors, based on some first rounds of studies, lead researchers anxious for important findings, and clinicians anxious for effective detection, to believe what are not very sound results? This must be the case, unless the early studies were seriously flawed in their methodology.

Probably more importantly, this reflects a profound modern-day problem in science: the way that complex, multi-factor causation is studied by statistical studies, and the difficulty of getting good enough samples, well-enough understood, to generate reliable results. Plus, many factors are lifestyle-related, and they change over time.

But could these findings be a reflection of a point we often wonder about, and that applies to evolutionary reconstructions as well--namely, that the assumptions underlying statistical studies of these types make and test assumptions? Is it that the methods assume a type or level of regularity that simply does not reflect how things really are?

If that is the case then we have to await the next brilliant insight that will transform how we think. Meanwhile, we are apparently stuck not knowing why results and opinion change so often, or whether we can trust the latest study more than the previous studies it overturns.....or whether we have to believe that the latest study, too, will shortly be overturned.

Either the situation is straightforward but we just haven't done the right studies, or we're in a deeper epistemological hole than most people would like to think, calling for the kinds of creative thinking that no grant or research 'system' can order up, but simply depend on the lucky arrival of the required genius.

Thursday, September 13, 2012

Did you see the report (e.g., here on the BBC) of a 150 million year old fossil crab's last death walk? The trail it followed until it finally expired, where it (and the trail) were fossilized have been discovered and are fascinating. Here is the spoor it left in the sand (top is a photo of the fossil track, bottom the path of the track), poor thing:

This picture here shows the crab itself:

Now this is interesting for its own sake. but look at this image:

This one is contemporary, and you can see them along the tidal beaches in many places in our country and elsewhere.

What's interesting is how the horesehoe crab hasn't changed over so long a time. We are trained by textbooks, by Darwin himself (for those who actually read him), and of course by the media, to think of evolution as constantly happening in a relentless rat-race of competition, always needing to adapt to the changing environment or improved competitors.

But here is an organism that has been running the race by staying in place. In fact, at the DNA level the currently available data are scant, but this group of arthropods has continued to evolve, so that its DNA sequences reflect very distant common ancestry--for some groups that look like horsehoe crabs and the horseshoes themselves, hundreds of millions of years. That means that the accumulation of mutations in their DNA has continued to evolve more or less as would be expected.

Now much of the DNA that is used as a molecular clock to estimate species ancestral split times has little if any function and is chosen for study specifically for that reason, since it is more reliably clock-like than functional DNA that can be affected by quirky natural selection.

But if adaptation is so intense a pressure to change in response to one's surroundings, how is it that there has been essentially no evolution of functional aspects of the genome in 150 million years? The simple answer is "Well, no problem! Their environment hasn't changed." There's no easy way to refute that, though geological and paleoecological data might suggest otherwise. Environment is not just the temperature and salinity of the ocean, it includes networks of plants and animals, each preying on the other and so on. So it is perplexing that so little change has happened.

Perhaps horseshoe crab physiology is different enough to show selective pressures, and it's just the shell that hasn't changed. But the fossil anatomy is not just 'skin' (shell) deep, but is in so many of the details. Even just by chance one would expect that minor variations in the shape and shell structures etc. of these creatures would have arisen. Really, one should expect more than trivial changes.

There should be many ways to modify shape and stay 'fit'. Basic body plans are rather stable, but they do change, as we see by the variation among, say, fish and humans or wasps and butterflies. One might say that the crabs' shape is determined by just one or two genes that controls so many of the conserved parts. Then, any mutation might be harmful and removed.

But developmentally, such traits and complexity rarely, if ever, is so simple and usually involves many different genes' contributions. So how such conservation has happened--and there are other examples such as flies or ants entombed in millions-years old amber etc., who look just like our friends and pests today--is rather mysterious, and very interesting to try to explain in terms of our current knowledge of developmental and population genetics.

So, eons later, we have the last walk of this poor doomed crab. But although it was going somewhere as its spirit left its shell for the Other World, its lineage wasn't going anywhere at all.

Wednesday, September 12, 2012

On Monday we described the existence of subglacial lakes in Antarctica (and elsewhere in the solar system), and the effort to bore into them to sample their water and surfaces. Geochemists and geologists have various questions they'd like to answer about this interesting phenomenon. Such ice sheets initially form on the surface just as it does in the winter where you and we live, but in an ever-winter climate it never thaws. As it becomes ever thicker, the insulation it provides from solar heating, the pressure at its base, and geothermal heating from below melt water at the earth-glacier interface--it liquifies the ice there. The water then builds up over time in to a sizable lake, and will naturally also follow available ground channels to connect with other such lakes and so on. Maybe even to connect to subsurface water.

On Earth, there is an old saw that where there's water, there's life, so one question is whether that is a rigorous enough theory to suggest that there's life in these subglacial Antarctic lakes. And since there is similar subglacial liquid water elsewhere even in our own solar system, such as on Jupiter's moon Europa, the question is naturally raised as to whether there's life there, too. Or all over the universe.

Do Earthly matters matter?
What would we expect to find in water samples brought up from probes into Antarctic subglacial lakes? Well, we know that millions of years ago, there were complete living ecosystems, even tropical in their abundant and diverse life. So, if they could last long enough, remnants must have once been on the surface when it initially froze over and could still be there today. That would range from what would now be fossils, to perhaps the kind of frozen, mineralized microbial life that has been found at the surface of Antarctica. So it would be no total surprise to find that kind of evidence (though this project is not going to bore into the ground surface below the lake, where fossils of multicellular organisms might be most likely to be found). We have to leave such speculations to geologists and paleontologists.

One could also not be surprised if there are organic molecules in the water that were once part of that ancient life, and were embedded in the initial ice layer as it formed. Conditions may have been stable enough that such molecules didn't degrade. DNA is unlikely to have been preserved intact, but many kinds of molecules and perhaps even nucleotides (DNA building blocks) might have survived the Long Chill. Finding them would be at most mildly interesting (since we know they must have been there at one time). Organic molecules continually rain down on Earth from space, so they would have landed on the forming ice, and hence be in the melted subglacial water.

Since we know that fish and many other types of life have adapted genetically to be able to live in the frigid waters around the poles, could we find them in these subglacial lakes? It seems unlikely, to us at least, for several reasons. First, terrestrial life would have had to survive the long eons of climate cooling and then unmelting snow, eventually covering the entire surface leaving nothing to eat, and then somehow adapted to live embedded in ice for millions of years until the Big Thaw at the bottom. So this seems highly unlikely and we doubt the lakes' explorers expect that kind of life.

Darwinian adaptation can be remarkable, but it seems to be a stretch in this case, unless signs of life that were found were from things that seeped up from underground or from the surrounding oceans.

Perhaps micro-organisms could have adapted to the cold, but where would they have lived during the millions of years that the earth-glacier interface was frozen solid? It would probably have had to be under the surface, surviving and adapting somehow until a liquid lake formed--perhaps they lived in underground liquid water and then seeped into the subglacial lake as it formed?

Most likely one would find simply signs of life--molecules of life, but that would in itself tell us nothing since it would be expected for the above reasons (that there was life there before the freeze). In a way, perhaps we would be surprised not to find such molecules, though in this case the planned samples will be small--only a few hundred ml of liquid--so a very chancy sampling of the lake.

So, one wonders just what the evidence for life would be that would be any sort of surprise. Even if it's true that on earth where there's water there's life, it doesn't mean that the 'life' is alive. It would take some clever argument to suggest how adaptations would have been possible unless as we suggested above it were from subterranean water and/or perhaps had some deep channels to the water surrounding Antarctica.

In any case, it will be interesting to see what is found. It may tell us things about geological history and processes. And maybe we, not geologists, are missing some points of the goals of the expedition that didn't come through in an interview program on the BBC or on the Wiki pages devoted to subglacial lakes.

Life in spaceBut what about the sexy hint that it will tell us about life on ice-bound orbs like Europa? Just because, or if, it's true that where there's water there's life on earth, has no bearing whatever on the relevance of this kind of generalization elsewhere. Water is compatible with life, at least life as we know it here, and life evolved from watery beginnings and hence depends on water, but water doesn't cause life. What's in the liquid water under Europa's icy coat may be interesting for all sorts of reasons, but to justify it on the grounds of it being evidence for life, and using Earth as a precedent, is the kind of stretch that can be very misleading.

The public is hungry for science stories (and for science fiction), and NASA does big business in 'astrobiology', at least partly if not mainly as a marketing component. And if half our population doesn't believe that evolution took place, how can we expect them to be able to discriminate the fairy tales used to justify the cost of space exploration? Maybe it would be better to be a bit more critical in what is said to scientists and public alike, about the value and interest in simply learning more about the universe--genuine excitement about the genuinely interesting knowledge of existence that can be gained. Or, equally, whether that value is worth the cost given other problems that people face here on the surface, where it's warm and indisputably lively.

Tuesday, September 11, 2012

Our favorite tweet about ENCODE went something like this: "I have no idea what ENCODE is but I know it's making everyone mad." There were valid reasons for all the to-do, but we want to go beyond that here and talk about the science.

The ENCODE project is a large-scale genomewide attempt to "build a comprehensive parts list of
functional elements in the human genome." The idea is that once we know what does, and what doesn't, have function, we can effectively home in on those sites that affect human traits and, of course, disease susceptibility in particular. The new ENCODE web page will be very helpful and welcome.

Yes, the hoopla surrounding the release (or is it 'press release'?) of the ENCODE results was widely criticized, including by us, for its excesses and manifest if not blatant self-promotional advertizing. The critiques included comments about possible over-acceptance of data that are less secure than the impression given, and other such issues.

These critiques are justified, and it will take an enormous almost open-ended effort to address or resolve all of the points that have been raised--if that were even possible, given life's moving target. And, of course, this must already have triggered a host of me-too demands by the mouse, fly, nematode, arabidopsis, maize, and other genome communities who will want to do all the same for their favorite species--and of course, they'll make the same claims about its urgent disease relevance. Adjudicating the relative importance of what to fund may be tricky if budgets are limited.

As importantly, a sober evaluation of what and where the real value is may be contentious. This is because if causation is complex and much or most of the genome is involved in traits of interest, exhaustive enumeration of countless trivially-small or rare-variant effects may not have much point, even if each instance is really valid, which will be hard to prove. Like trying to understand a changing beach by enumerating sand grains. Our earlier post dealt with some of these points.

However, there is one major actual scientific point that even in this sea of potential error or misinterpretation, seems rather safe--and particularly important.

Making life live
The traditional idea of genomes is that their purpose is to code for protein. We've long known that DNA has to replicate itself and that it strings along tens of thousands of protein-coding segments, and that these functions are fundamentally important to life. Life is about proteins and the variation among cells and among species is largely due to variation among proteins. Some DNA codes for RNA that is directly functional rather than being translated into protein. We've known all this for many decades.

We've also known for somewhat fewer decades that part of DNA is used to determine which of our thousands of genes are expressed (used) in which of our cells and under what conditions. This is called regulatory DNA. A body is made of many cell types (skin, nerve, muscle, stomach, immune,....) and they are different because they use different sets of genes. Likewise, cells change the genes they use, or their level of activity, based on circumstances. That is why organisms can respond to changing environmental conditions and so on. This works because the regulatory DNA is recognized by proteins (transcription factors) that stick there, and that leads to other proteins transcribing nearby DNA into RNA.

We knew that regulatory DNA was just as important as coding DNA, so that there are two basic types of 'code'. In Mermaid's Tale we called these correspondencecodes and recognitioncodes, respectively. The first term refers to DNA whose sequence corresponds to the protein (or functional RNA) that is copied from it and used elsewhere in the cell. The second is a sequence code that is directly used--recognized by transcription factors--rather than only standing for something used elsewhere. The transcription factors themselves are proteins, and so must be coded for by their own correspondence codes somewhere in the genome.

The dogma for a long time was that protein variation is the cause of evolutionary fitness differences and trait variation. This followed essentially from Mendel's showing that what turned out to be protein variation--and hence variation in protein-coding genes--was responsible for trait differences in peas. That led to a century of focus on genes as protein correspondence codes, the discovery of how that worked and how those genes were arranged on chromosomes.

But a few decades ago recognition codes were discovered, and that explained in principle how DNA also coded for the usage of its genes. None of this was or is controversial. But gene mapping to find genes 'for' (causally associated with) traits, and especially (from a funding point of view) disease, initially was intended to find the protein variants that were responsible. This was the focus and the prior belief of most investigators, but genomewide association studies, GWAS, were conceptually designed for that purpose, and it was obvious that regulatory variation would also be picked up by the same method.

Although the media and grant attention has focused on protein variation, even for years after we knew about the importance of regulation, it has turned out that many if not most well-documented mapping-identified common disease variants were not in protein coding regions. And the important documentation of the ENCODE project shows rather persuasively and systematically, that the finding of regulatory rather than coding variation in the data that has been has been a valid indicator of how things are.

The important impact of this is to make it clearer that most of our functional DNA is not about protein-codes directly, but is about how they are used. It is the timing among cells, and regulation of that among cells, of the genes and their level of expression, that accounts for the production of organisms from fertilized eggs (single cells), and likewise that their variation and hence how they are seen by natural selection is important to evolution. In a sense, overall, evolution is a regulatory phenomenon.

What needs rethinking?
The ENCODE project did not raise any new points in this regard but the paper by Maurano et al. in the Sept 7 Science, "Systematic Localization of Common Disease-Associated Variation in Regulatory DNA," that shows the regulatory documentation from the project is an important one to be aware of. And this paper only deals with classical 'regulatory' regions, but not with other kinds of DNA-encoded RNA molecules of various sorts that serve to regulate gene usage and dosage in other ways (others of the ENCODE papers in various places deal with some of these issues)

The finding that much or most of DNA function is regulatory casts a somewhat different light on the nature of organisms and on their evolution, but it is not a fundamental new theory of any sort. Let's hear no talk of 'paradigm shifts' or any other such puffery! Though we continue to learn of new DNA function and that more of the DNA has function that was thought at one time, the results are just a re-weighting of focus among things we've long known. It's an incremental accumulation of knowledge. Indeed, traits and their evolution and variation are still mainly about protein structure and variation, and that ultimately means genomic structure and variation.

Conceptually, however, by trying to understand regulation, we gain a better way to view ourselves as 'emergent' phenomena, that is, that an organism and its highly complex organization is more than just a pile of genes, but 'emerges' from the way those genes are used. This is similar to the idea that you cannot understand a building by enumerating the bricks, tiles, wires, and so on that it is built of--or sand grains and beaches.

And, importantly, the new project makes traits more, not less, complex and potentially problematic to deal with. This is because it simply adds to the breadth and depth of factors whose variation contributes to the nature and variation of our traits. Similarly, every new factor that we find contributing in subtle, and subtly variable ways to traits of interest, the harder it is to promise that we can enumerate risk gene by gene, or account for genome evolution by gene-focused selection models. Different ways of thinking will be called for.

So, filter out the blatant BS, and there is still importance in the findings.

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